Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6

Toshinori Unno, Minoru Wakamori, Masato Koike, Yasuo Uchiyama, Kinya Ishikawa, Hisahiko Kubota, Takashi Yoshida, Hiroko Sasakawa, Christoph Peters, Hidehiro Mizusawa, Kei Watase

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by the expansion of a polyglutamine tract in the Cav2.1 voltage-gated calcium channel. To elucidate how the expanded polyglutamine tract in this plasma membrane protein causes the disease, we created a unique knockin mouse model that modestly overexpressed the mutant transcripts under the control of an endogenous promoter (MPI-118Q). MPI-118Q mice faithfully recapitulated many features of SCA6, including selective Purkinje cell degeneration. Surprisingly, analysis of inclusion formation in the mutant Purkinje cells indicated the lysosomal localization of accumulated mutant Cav2.1 channels in the absence of autophagic response. The lack of cathepsin B, a major lysosomal cysteine proteinase, exacerbated the loss of Purkinje cells and was accompanied by an acceleration of inclusion formation in this model. Thus, the pathogenic mechanism of SCA6 involves the endolysosomal degradation pathway, and unique pathological features of this model further illustrate the pivotal role of protein context in the pathogenesis of polyglutamine diseases.

Original languageEnglish
Pages (from-to)17693-17698
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number43
DOIs
Publication statusPublished - 2012 Oct 23

Keywords

  • Cerebellum
  • Inherited ataxia
  • P/Q-type calcium channel

ASJC Scopus subject areas

  • General

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